DE2026080C3 - 5-methyl-10- (ß-alkylaminoethyl) - dibenzothiazepines, processes for their preparation and pharmaceutical compositions - Google Patents

Description

The invention relates to 5-methyl-10 - (/ i-aI-kylamino £ ihyl) -dibenzo- (b, i) -azepines, a process for their production and pharmaceutical compositions containing them according to the claims.

The salts of the compounds of the general formula (I) with mineral acids or organic acids are salts with therapeutically acceptable acids such as hydrochloric acid, phosphoric acid, citric acid, Malic acid, benzoic acid and fumaric acid.

The new dibenzoazepines of the formula I have interesting pharmacological properties.

In particular, they have a thymoanaleptic effect.

The preferred dibenzoazepines of these compounds are:

5-methyl-10 - (/ f-dimethylaminoethyl) -dibenzo- (b, f) -azepine and its hydrochloride,
5-methyl-IO - (^ - monomethylaminoethyl) -dibenzo- (b, 0-azepine and its hydrochloride,
2-chloro-5-methyl-l (M / '- dimethylaminoethyl) -dibenzo- (b, l) -azepine and its fumarate,
7-chloro-5-methyl-10 - (/ f-dimethylaminoethyl) -

dibenzo- (b, f) -azepine and its fumarate,
7-chloro-5-methyl-10 - (/ i-monomethylaminoethyl) -dibenzo- (b, l) -azepine and its fumarate,
8-chloro-5-methyl-10 - (/? - dimethylaminoethy!) - dibenzo- (b, f) -azepine and its fumarate.

The class of dibenzoazepines, whose antidepressant properties are known, is already known. !In The best-known representatives of this class of products are imipramine, desipramine or the dibenzepine.

This type of product is essentially characterized by its thymoanaleptic effect, i. H. through the possibility of turning the state of mind into its opposite, which one in melancholy, anxious or neurasthenic patients.

The dibenzoazepines generally have a certain advantage over the monoamino oxidase inhibitors, whose effect is less constant and is often accompanied by dangerous after-effects. Dibenzoazepine however, had the disadvantage that they also had a sedative psycholeptic effect or had an anticholinergic effect to varying degrees according to the molecules.

It was therefore desirable to find compounds in this class of thymoanaleptic agents whose effect is stronger and their after-effects are reduced are.

The compounds of general formula I meet this therapeutic requirement. You own itself also has a thymoanaleptic effect that is clearly superior to that of dibenzepine. It was in particular proven in animals through the antagonistic effect on neuroleptics such as reserpine and tetrabenazine, due to the increasing effect on amphetamine and dihydroxyphenylalanine (DOPA) in animals previously sensitized by a monoaminooxidase inhibitor. This superior effect of the compounds according to the invention is evident from the test report below evident.

They can thus be administered without one has to fear that one must observe drowsiness in patients, which is a consequence of the sedative

tive effect or visual disturbances resulting from an effect of an atropine type.

They can be used orally, transcutaneously or rectally and can be in the form of lozenges, coated lozenges, injectable solutions or suspensions and in the form of suppositories, where the forms for pharmaceutical use are produced by known methods.

The useful administration of these compounds is between 25 and 500 mg per day in adults depending on the type of administration and the sensitivity of the patient to be treated.

The unit dosage is generally 25 mg, preferably in the form of tablets.

The inventive method is illustrated in the scheme and characterized in that one Salt of a compound of the general formula

where X and X 'have the abovementioned meaning and "alc" means a lower alkyl radical, to one Compound of the general formula

COOalc

(III)

CH ₃

reduced this in the presence of an alkaline agent with a 2-halo-l-dialkylaminoethane of the general formula

Hal-CH ₂ CH ₂ N

(Vl)

where Hai represents a halogen atom, to a compound the general formula

R ₁

NH ₂ CH ₂ C COO alc

X '(IV)

CH ₃

converts this compound with the help of a hydride

a compound of the general formula

NH ₂ CH ₂ C CH ₂ OH

CH ₃

reduced, this compound under the action of a dehydrating agent to a compound of the general formula

R ₁

CH ₂ CH ₂ N

or an organoiuminium compound, such as aluminum triisobutyl, is used instead;

the dehydrating agent may be Lewis acid, sulfuric acid. Phosphoric anhydride.

Be phosphoric acid or p-toluenesulfonic acid;

as dealkylating agent one can use a low-

(V) alkyl chloroformate, the alkyl radical of which is 1 to 4 carbon

owns lenstoffatonie, or a cyanogen halide, such as

ίο use cyanogen chloride or cyanogen bromide;

the alkaline treatment is carried out with the help of sodium hydroxide or potassium hydroxide;
you can purify the 9-alkoxy-carbonyI-9 - (/ i-dialkylaminoäthyiji-10-methylacridan of the formula IV by forming a salt of this compound by releasing the free base with the help of a basic agent such as sodium hydroxide, which is used in particular as a salt-forming agent an acid is used, such as an organic diacid or, in particular, fumaric acid.

there)

reacts and this compound, if desired, the action of a dealkylating agent, followed by an alkaline treatment to form a compound of the general formula

(Ib)

X '

CH ₃

subjected and, if desired, by the action of a mineral acid or an organic acid the compounds formed are converted into their salts.

The 9-alkoxycarbonyl-10-methyl-acridinium salt used as the starting material of the general formula II can easily be analogous to a process such as it by R a u h u 1 and KoII. (J. Org. Chem. 30, 3587, 1965), where the The salt used can be the chloride or the sulfate, preferably 9-methoxycarbonyl-10-methyl-acridinium methyl sulfate is used.

The method according to the invention can also be characterized by the following features:

To reduce the compound of the general formula II, an alkali metal borohydride, such as Potassium borohydride or sodium borohydride, or hydrogen in the presence of a hydrogenation catalyst, such as platinum or palladium, is used will;

an alkali metal, such as potassium or sodium, or an alkali metal alcoholate, such as potassium tert-butoxide, can be used;

Hal in the general formula VI can be chlorine, bromine or iodine;

as hydride, lithium aluminum hydride, aluminum hydride, diborane or an organoaluminum hydride, such as aluminum diisobutyl hydride.

Test report
I. Antagonistic Effects

a) Reserpine antagonism

The investigation of this effect is carried out at the

Rat by determining the ptosis of the eyelid.

caused by reserpine. The ptosis is determined on the basis of the following standard of evaluation (0 to 4) determines:

0 = eye normal: fully open.

1 = Lidspalie reduced by a quarter.

2 = eyelid gap reduced by half.
3 = eyelid gap reduced by three quarters.

4 = eyelid gap completely closed.

The assessment of ptosis is made every hour during

a period of 6 hours after intraperitoneal administration of 1 mg / kg reserpine.

The results are given by the DA ₅₀ . di is the dose that achieves a 50% protective effect against the control samples.

b) Tetrabenazine antagonism

Tetrabenazine causes ptosis of the eyelids in rats, the antidepressant agents can decrease. The evaluation of the ptosis is carried out in the same way as in the previous test (for determination of reserpine antagonism).

The ptosis is determined 30 minutes, ₁ hour, 2 hours and 2 hours after the intra-peritoneal injection of 10 mg / kg tetrabenazine.

The results are given O ₅ based on the DA.

II. Potentiation effects

a) Potentiation of the effect of DOPA
(dl-3,4-dihydroxyphenylalanine)

to the intraperitoneal injection of DOPA Mice exposed to lproniazid injection 18 hours prior to testing sensitized, causes several symptoms of arousal: muscle hypertension, agitation. Aggressiveness, screaming, salivation,

b5 Exophthalmic The intensity of each observed Symptoms is rated from 0 to 3.

The previous administration of antidepressant agents significantly potentiates these effects

The doses of DOPA (100 mg / kg) and Iproniazid (50 mg / kg) are such that the states of excitement in the control lieres (treated only with these substances) are only weak in order to improve the potentiating effectc to be observed depending on the dosage of the anlidepressant agent can.

The results are shown using the DA + 50%, the dose at which the effect is 150% of the effect achieved in the control samples.

b) Potentiation of the apomorphine effect

The subcutaneous injection of 5 mg / kg apomorphine induces several stereotypical movements in the mouse out: chewing, licking, muscle hypertension, agitation, their intensity (rated from 0 to 3) 10, 20 and 30 minutes after the injection is determined. The anlidepressiv acting means polish this Effects.

The results are given using the DA + 50%.

III. Acute toxicity study

The DL ₅ I of the various products was determined after intraperitoneal administration to the mouse. The determination of the mortality was carried out after 48 hours.

The DL ₅₀ and the results of the other experiments are summarized in the table below.

link Reserpine Tetra DOPA Apo- DL ₅₀ according to the example Antagonistic benazin- Potential morphine (Mouse) mus Antagonistic decoration l'olcn- DA ₅₀ mus DA + 50% zicrung DA ₅₀ DA + 50% (mg / kg) (mg / kg) (mg / kg) (rag / kg) (mg / kg)

2
3
5
6th

Dibenzepine

1.5 15 15

20th

5 3

<0.2 5 3

15th

0.6

10
20th

10

2-5
2
5

10 5

18th

50
75
35
80
80

The present invention is further illustrated with the aid of the following examples.

example 1

5-methyl-10 - (/ <- dimethylaminoethyl) -dibenzo- (b, f) -azepine

Level a
9-methoxycarbonyl-IO-methyl-acridan

78 g of 9-methoxycarbonyl-10-methyl-acridinium methyl sulfate are mixed (obtained according to the method as described by R a u h u t and KoII., J. Org. Chem. 30, 3587, 1965), 800 ecm Ethanol and 40 ecm of distilled water, then add 80 g over 45 minutes at room temperature Potassium borohydride added. The mixture is stirred for 30 minutes, poured into an ice / water mixture and stirred

... öV.ror. ^ 1 1 Cliin ^ on ", Ι,., Ι, ^ Η _m , l ΆΊΙ,., .- ..". Ι Λ,. \

nuiitbiiu - LJiUi] UVIi, vaiiuiiivii um JiIIILI uiiu lil »:) lll brings the extract to dryness in a vacuum. 51 g of 9-meloxy-carbonyl-10-methyl-acridane are obtained in the form of a solid, pale yellow product which is soluble in ethylene chloride, ether and ethyl acetate, is insoluble in water and melts at 106 "C.

For analysis, the product is recrystallized from isopropyl ether by means of heat and cold, the Melting point does not change.

Analysis for QhH ₁₅ O ₂ N = 253.31: Calculated ... C 75.87, H 5.87, N 5.63%; found C 75.9, H 5.9, N 5.7%.

I. R. spectrum (chloroform):

Presence of C = O at 1728 cm " ^1. Presence of aromatics at 1595 and 1475 cm" ¹ . Level B.

9-methoxycarbonyl-9 - (/ i-dimethylaminoethyl) -10-methyl-acridane (Fumarate)

36.5 g of 9-methoxycarbonyl-10-methyl-acridane and one liter of toluene are mixed, 50 ecm of toluene is distilled off and the mixture is cooled. Is added 5.65 g of potassium added at a temperature below +10 ⁰ C, stirred for 2 hours at room temperature, heated for 30 minutes to reflux and cooled. A solution of 52.5 ecm 2-chloro-1-dimethylaminoethane in 200 ecm toluene is added at a temperature below +20 ° C., the mixture is refluxed for 24 hours, cooled and 100 ecm tert-butanol is added. The mixture is stirred for one hour at room temperature, 35 ecm of ethanol is added

Add ίο and stir for 30 minutes at room temperature. It is extracted with 2N hydrochloric acid, the acidic phases are washed with ether and made by adding of caustic soda alkaline, extracted with ether, washes the ether phases with water, dries over Magnesium sulfate and distilled to dryness in vacuo. The residue is dissolved in 100 ecm Methanol, add 300 ecm of a saturated fumaric acid solution in methanol and distilled by to replace methanol, ethyl acetate is added.

It is seeded for crystallization, cooled for 30 minutes, filtered off with suction, and the precipitate is washed with water and dry it. 37 g of 9-methoxycarbonyl - 9 - (/ i - dimethylaminoethyl) - 10 - methylacridane are obtained (Fumarate) in the form of a solid product that is soluble in methanol, slightly soluble in ethyl acetate, insoluble in water and that melts at 176 ° C.

For analysis, the product is crystallized by dissolving it in methanol and adding ethyl acetate

and concentration around, the melting point remaining unchanged.

Analysis door C ₂₄ H ₂₈ O ₁₁ N ₂ = 440.48:

Calculated ... C 65.44, H 6.41, N 6.36%;

found C 65.5, H 6.4 6.3. N 6.3 6.4%.

I. R. spectrum (Nujol):

Presence of C = O bands at 1728 cm "' (Ester) and 1700 cm '(acid).

Level C

9-hydroxymethyl-9 - (/ f-dimethylaminoethyl) -

10-methyl-acridane

1.) Return to the base

50 g of 9-methoxycarbonyl-9 - (/ i-dimethylaminoethyl) -10-methyl-acridan are added (Fumaral) in suspension in 500 ecm of water, cools and gives Add 30 ecm of sodium hydroxide solution. It is extracted with methylene chloride and the organic phases are washed with Water, dried over magnesium sulfate and distilled to dryness in vacuo. 36 g of 9-methoxy-2> are obtained carbonyl - 9 - (/ ί - dimethylaminoethyl) - 10 - methylacridane.

2.) reduction

400 ecm of tetrahydrofuran are cooled, 20 g of lithium aluminum hydride are added over the course of 15 minutes and then a solution of 36 g of 9-methoxy-carbonyl-9- ((i- dimethylaminoethyl) -! 0-methyl-acridane in 400 ecm tetrahydrofuran. the mixture is heated reflux for 2 hours, cooled and added 200 cc of tetrahydrofuran added with 20% of water at a temperature below 0 ⁰ C. It is filtered off, washed with methylene chloride, distilled to dryness in vacuo, the residue is dissolved in methylene chloride The organic phases are washed with water, dried over magnesium sulphate and concentrated with the addition of ethyl acetate to replace the methylene chloride hydroxymethyl-9 - (/ i-dimethylaminoethyl) -l0-methyl-acridan, sparingly soluble and will melt in the form of a colorless solid product which is soluble in methylene chloride in ethyl acetate and insoluble in water at 150 ⁰ C.

Concentration of the mother liquors gives a second yield of 1.6 g of the product (total yield: 79%).

For analysis, the product is crystallized by dissolving it in methylene chloride and adding ethyl acetate around, the melting point remaining unchanged.

Analysis for C ₁₉ H ₂₄ ON ₂ = 296.40:
Calculated:

C 76.99, H 8.16, N 9.45%;

calculated with V4-M0I ethyl acetate:

C 75.5, H 8.2, N 8.8%;

found:

C 75.3-74.4, H 8.5-8.1, N 8.8-8.6%.

60

1. R. spectrum (chloroform):

Presence of —N <at 2780 cm " ¹ .
Presence of —OH.

b5

Level D

5-methyl-10 - (/ i-dimethylaminoethyl) -dibenzo- (b, f) -azepine

A mixture of 24.5 g of 9-hydroxymethyl is heated - 9 - (/ i - dimethylaminoethyl) - 10 - methylacridan, one liter of m-xylene and 125 g of phosphoric anhydride under reflux for 3 hours. One cools down the reaction mixture is poured onto ice, stirred for 15 minutes and made by adding sodium hydroxide solution alkaline. It is extracted with ethyl acetate, the organic phase is washed with water and dried over magnesium sulfate and distilled to dryness in vacuo. The residue is dissolved in ether, filtered, concentrates in small volume and adds pentane as it distills to drive off the ether. It is filtered, concentrated to about 100 ecm, inoculated to crystallize, cools for one hour, sucks off, washes the precipitate with water and dries in vacuum. 16 g of 5-methyl-10 - (/ i - dimethylaminoethyl) - dibenzo - (b, f) - azepine are obtained in the form of a yellow solid product that dissolves in alcohols, ethers, ethyl acetate and in chlorinated solvents is soluble that is sparingly soluble in pentane and insoluble in water and that melts at 78 ° C (yield: 70%).

For analysis, the product is chromatographed on magnesium silicate, eluted with ether and crystallized by heating and cooling from pentane. The melting point does not change.

Analysis door C ₁₉ H ₂₂ N ₂ = 278.38:

Calculated ... C 81.97, H 7.97, N 10.06%;
•• found .... C 82.0, H 7.9, N 9.9%.

IR spectrum (chloroform):
Presence of C = C at 1634 cm " ¹ .
Presence of —N- ^

UV spectrum:
1.) In ethanol:

Max. At 215 ma Ej * = 932.
Max. At 254 - 255 ηΐμ Ej * = 1122.
lnfl. around 281 ΐημ Ej ^ _n , = 156.
Max. At 331 ΐτίμ Ej ^, = 47.

2.) In ethanol / n / lOHCl:

Max. At 214 - 215 ηΐμ Ej * = 929.
Max. At 252 - 253 πΐμ Ej * = 1074.
lnfl. around 280-281 ΐτίμ EJ ^ _n = 167.
lnfl. around 326-327 πΐμ Ej * = 46.

3.) In ethanol, n / 10NaOH:
Max. At 254 ΐτίμ Ej * = 1085.
lnfl. by 326 m | i Ej * = 50.
lnfl. around 280 ΐημ Ej * = 159.

Example 2

5-methyl-10 - (/ <- monomethylaminoethyl) -dibenzo- (b, f) -azepine (Hydrochloride)

Level a

S-methyl-lO-i / i-N-ethoxycarbonyl-N-methylamino-

ethyl) -dibenzo- (b, f) -azepine

32.5 ecm of benzene and 6.5 ecm of ethyl chloroformate are mixed and then gives a solution of 6.5 g of 5-methyl-10 - (/ i-dimethyIaminoäthyl) -dibenzo- (b, f) -azepine (obtained in example 1) in 32.5 ecm

Benzene is added and the mixture is refluxed for 5 hours. The mixture is cooled, ethyl acetal is added and the mixture is stirred with I n-hydrochloric acid, decant the organic phase, wash it with water and dry it over Magnesium sulfate and distilled to dryness in vacuo. 5 g of 5-methyl-IO - (// - N-ethoxycarbonyl - N - methylamino - ethyl) - dibenzo - (b, Q-azepine, which is used as it is in the next stage (yield: 64%).

IR spectrum (chloroform):
Presence of carbonyl at 1687 cm "'.

Level B.

5-methyl-10 - (/ i-monomethylaminoethyl) -dibenzo- (b, f) -azepine (Hydrochloride)

A solution of 5 g of potassium hydroxide in 50 ecm of butanol is added to 5 g of 5-methyl-IO - (/ iN-ethoxycarbonyl-N-methylaminoethyl) -dibenzo- (b, f) -azepine, and the mixture is stirred and refluxed for 20 hours . The butanol is distilled off in vacuo, the residue is taken up in water, extracted with ethyl acetate and the organic phases are washed with water, dried over magnesium sulfate and distilled to dryness in vacuo. The residue is dissolved in 10 ecm of ether, the solution is chromatographed over magnesium silicate, eluted with ether and distilled to dryness in vacuo. 3.5 g of crude 5-methyl 1 -10 - (ß - monomethylaminoethyl) - dibenzo - (b, f) -azepine are obtained, which is dissolved in 30 ecm of ethyl acetate. A solution of anhydrous hydrochloric acid in ethyl acetate is added, the mixture is cooled for 30 minutes, suction filtered and dried, and 3.5 g of the crude compound is obtained, which is purified by refluxing and concentrating it by dissolving in benzene. After the crystallization is inoculated, it is filtered off with suction, the precipitate is washed with water and dried. 2.65 g of 5-Me-Ih yI -10 - (ß - monomethylaminoethyl) - d ibenzo - (b, f) -azepine hydrochloride are obtained in the form of a solid yellow product which is soluble in alcohols and methylene chloride, slightly soluble in benzene and ethyl acetate, insoluble in water and ether, and that melts at 180 "C.

Analysis for C ₁₈ H ₂₁ N ₂ CI = 300.83:

Calculated ... C 71.87, H 7.04, N 9.31, Cl 11.79%; found .... C 72.1, H 6.7, N 9.2, Cl 11.8%.

Example 3

8-chloro-5-methyl-10 - (/ <- dimethylaminoethyl) -dibenzo- (b, f) -azepine

Level a
2-chloro-9-cyano-acridine

A mixture of 1 g of 2,9-dichloro-acridine (obtained according to the process as described by M. Bogucka [Roczniki Chem. 40, 677, 1966]), 230 mg of sodium cyanide and 20 ecm is heated in a closed tube Methanol at 140 ^° C. for 4 hours; it is cooled, filtered, the precipitate is washed with acetone and dried; the product is purified by sublimation in vacuo at 0.1 mm Hg and 530 mg of 2-chloro-9-cyano-acridine are obtained in the form of a yellow solid product that is soluble in chloroform, slightly soluble in alcohol, insoluble in water, ether and benzene, and that melts at 208 "C.

Level B.
2-chloro-9-carboxy-acridine

A mixture of 19.8 g of 2-chloro-cyanacridine and 120 ecm of 90% sulfuric acid is heated to 100 ° C. for 3 hours, cooled to 15-20 ° C., a solution of 15 g of sodium nitrite and 30 ecm of water is added and the mixture is heated the reaction mixture for 2 hours at KX) ¹ C. It is cooled, poured into an ice / water mixture, filtered off with suction, the precipitate was washed with water and extracted with a 10% aqueous sodium carbonate solution, acidified by adding 6N hydrochloric acid, The precipitate is filtered off with suction, washed with water and dried, giving 10.6 g of 2-chloro-9-carboxy-acridine, which is used as it is in the following stage.

Level C
2-chloro-9-methoxycarbonyl-acridine

4.9 g of 2-chloro-9-carboxy-acridine are suspended in 5 ecm of methylene chloride at room temperature 60 ecm of a solution of diazomethane in methylene chloride added, which contains 17.9 g per liter, stirred for one hour and 30 minutes while passing in Nitrogen to remove excess diazomethane. The methylene chloride solution is washed with an aqueous 10% sodium carbonate solution, then with water, dried over magnesium sulfate with activated charcoal, filtered and evaporated to dryness. The residue is crystallized from boiling Methanol and 3.2 g of 2-chloro-9-methoxycarbonyl-acridine are obtained in the form of a solid, pale yellow Product that is soluble in chloroform, slightly soluble in ether and alcohol, insoluble in water and that with 130 "C melts.

Level D

2-chloro-9-methoxycaΓbony! -10-methyl-acridinium methyl sulfate

Dissolve 5 g of 2-chloro-9-methoxycarbonyl-acridine in 25 cc of toluene, are 25 cc of methyl sulphate are added and the solution was heated for 3 hours at 100 ⁰ C, cooled, added 50 cc of toluene, filtered off with suction, the precipitate is washed with toluene, then with ether and dry it. 5.4 g of 2-chloro-9-methoxycarbony 1-10-methyl-acridinium methyl sulfate are obtained, which is

as it is, used in the next stage.

Level E.

2-chloro-9-methoxycarbony) -10-methyl-acridane

5.4 g of 2-chloro-9-methoxycarbonyl-10-methyl-acridinium methyl sulfate are added suspended in 50 ecm of methanol and 2.5 ecm of water, gives 5 g of potassium borohydride added, keeps the temperature at 35-40 ° C, then stir for 30 minutes at room temperature; pours into a mixture of ice / water, sucks off, wash the precipitate with water and with chilled methanol and dry it. 3.45 g are obtained 2 - chloro - 9 - methoxycarbonyl - 10 - methyl - acridan in the form of a solid colorless product, which in Alcohol and chloroform is soluble, slightly soluble in ether and insoluble in water and that at 166 "C melts.

Level F

Level H

2-chloro-9-methoxycarbonyl-9 - (/ y-dimethylaminoethyl) -10-methyl-acridane

3.9 g of 2-chloro-9-methoxycarbonyl-10-methyl-acridane are dissolved in 10 ecm of tetrahydrofuran and 5 ecm of hexamethylphosphoric triamide, the solution is warmed to 45 ° C., 3.4 g of potassium tert-butoxide are added and the mixture is stirred for one hour at 45 to 47 ° C. 4.5 g / i-dimethylaminoethyl chloride are added, the mixture is stirred for 16 hours at 46 to 48 ° C., cools and 150 ecm of water are added, the mixture is extracted with ether and the washes organic phases with an aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and filtered and evaporated to dryness. 4.2 g of crude 2-chloro-9-methoxycarbonyl-9 - (β- dimethylaminoethyl) -10-methyl-acridane are obtained.

The 4.2 g of the crude product are dissolved in 15 ecm Methanol, a solution of 1.24 g of fumaric acid in 50 ecm of methanol is added, heated to reflux and the methanol is distilled off by replacing it with ethyl acetate.

The ethyl acetate is evaporated until crystallization begins, cooled for one hour, filtered off with suction, wash the precipitate with chilled ethyl acetate and dry it. 4.1 g of 2-chloro-9-methoxycarbonyl are obtained - 9 - (/ * - dimethylaminoethyl) - 10 - methyl-acridane (Fumarate). By concentrating the mother liquor, another 0.2 g of the product is obtained.

The 4.3 g of the fumarate are suspended in 20 ecm of water, the solution is brought to pH 8 to 9 for 15 minutes with stirring by adding sodium hydroxide solution, extracted with ether, the organic phase is washed with an aqueous sodium chloride solution and dried over magnesium sulfate , filtered and evaporated to dryness, giving 3.3 g of 2-chloro-9-methoxycarbonyl-9 - (ß -dimethylaminoethyl) -10-methylacridane (yield: 67%).

For analysis, the product is crystallized from isopropyl ether around.

The compound is in the form of a colorless solid product that dissolves in alcohol, ether, and chloroform is soluble, is insoluble in water and that melts at 106'C.

Level G

2-chloro-9-hydroxymethyl-9 - (/ i-dimethylaminoethyl) -10-methyl-acridane

14 ecm of tetrahydrofuran are cooled to OC, 0.9 g of lithium aluminum hydride is added and then a solution of 1.4 g of 2-chloro-9-methoxycarbonyl-9 - (/ i-dimethylaminoethyl) -10-methyI-acridane in 14 ecm Tetrahydrofuran, keeps the temperature below + 10 ⁰ C, heats the reaction mixture for 2 hours and 30 minutes under reflux, cools to 0 to 5 ° C and adds 10 ecm tetrahydrofuran with 20% _b0 water and then 50 ecm water. It is extracted with methylene chloride, filtered and the organic phases are washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness. 1.15 g of 2-chloro-9-hydroxymethyl- 9- (ß- dimethylaminoethyl) -10-methyl-acridane are obtained, which is used as it is in the next stage.

8-chloro-5-methyl-10 - (/ i-dimethylaminoethyl) -dibenzo- (b, f) -azepine

A mixture of 5 g of 2-chloro-9-hydroxymethyl - 9 - (/ i - dimethylaminoethyl) - 10 - methyl acridane is heated, 150 ecm xylene and 25 g phosphoric anhydride under reflux for 3 hours under nitrogen. It is cooled and the reaction mixture is poured

in an ice / water mixture, makes alkaline by adding 35 ecm sodium hydroxide solution, extracting with ethyl acetate, washing the organic phases with an aqueous solution of sodium chloride, drying over magnesium sulfate, treated with activated charcoal, filtered and evaporated to dryness. 3.9 g of the crude 8 - chloro - 5 - methyl - 10 - {"> - dirncthylaminoethyl) -dibenzo- (bf) -azepine are obtained.

The 3.9 g of the crude product are dissolved in 15 ecm Methanol, gives a solution of 1.2 g of fumaric acid in

2 »45 ecm of methanol are added, the methanol is distilled off by replacing it with ethyl acetate and allowed to crystallize out in the refrigerator for 48 hours. It is filtered off with suction, the precipitate is washed with ethyl acetate and dried. To give 2.8 g8-chloro-5-methyl-10 - (/ i-dimethylaminoethyl) dibenzo (b, 0-Aze-pin (fumarate), which melts at 150 "C and then at 164 C. By ¹ Cooling of the mother liquor is recovered; / wide phase of 0.25 g of the product.

3.05 g of the fumarate are dissolved in 20 ecm of water.

3d makes alkaline by adding sodium hydroxide solution, extracted with ether, wash the organic phase with an aqueous solution of sodium chloride, dry over magnesium sulfate and evaporated to dryness. By recrystallizing the residue in pentane

When heated, 1.72 g of 8-chloro-5-methyl-10 are obtained - (/) '- dimethylaminoethyl) - dibenzo - (b, f) - azepine in the form of a solid yellow product which is dissolved in alcohol, Ether and chloroform is soluble, insoluble in water and melts at 82 C.

Analysis for C ₁₉ H ₂₁ N ₂ Cl = 312.83:

Calculated ... C 72.95, H 6.76, N 8.95, Cl 11.34%:
found ... C 73.2. H 6.9, N 8.8, CI 11.3%.

I. R. spectrum (chloroform):

^A ' presence of C = C at 1627 cm' and aromatics at 1593 and 1573 cm ^-1 .

UV spectrum (ethanol):
;. At 217 Max _ηι μ. , = 28,200.
/ Max. At 257 πΐμ; , = 32,790.

Example 4

2-chloro-5-methyl-10 - (/ V-dimethylaminoethyl) -dibenzo- (b, f) -azepine

The mother liquors from the recrystallization of the fumarate from Example 3 (stage H) are evaporated to dryness and then by adding sodium hydroxide solution made alkaline. One leaches twice with ether, separates the ether phases, combines them, and washes them with it Salt water, dry over magnesium sulfate and concentrate. 1.7 g of a crude product are thus obtained which, as can be shown by thin-layer chromatography, is different from the compound of Example 3.

By chromatography on a silica column and eluting with a mixture of Cyclohexane / chloroform / triethylamine is separated again 0.4 ε of the connection from example 3 ah. the hot

79 C melts and then 0.5 g of a positional isomer compound of the compound of Example 3, namely 2 - chloro - 5 - methyl - 10 - (β - dimethylaminoethyl) -dibenzo- (b, f) -azspine, des ^ n physical data in the following are given.

U.V. spectrum (ethanol):

;. Max. 217 ma; > = 26 500.
;. Max. 257 m; > = 34,000.
Inflexion at about 285 mu
/. Max. 337 ηΐμ.

NMR spectrum

Changes in the area of the ethylenic and aromatic protons can be seen in comparison to the NMR spectrum of the compound of Example 3.

Analysis for C ₁₉ H ₂₁ N ₂ Cl = 312.83:

Calculated ... Cl 11.34, N 8.95%;
found .... Cl 10.7, N 8.6%.

Example 5

7-chloro-5-methyl-10 - (/ i-dimethylaminoethyI) -dibenzo- (b, f) -a: iepin

Level a
S-chloro ^ -methoxycarbonvl-acridine

5.7 g of 3-chloro-9-carboxy-acridine (obtained according to the method described by G r a i g and KoII., J. Org. Chem. Soc. 26, 135, 1961) in 50 ecm of methylene chloride in suspension, cools, gives 200 ecm of a solution of diazomethane in methylene chloride added and stirred for 15 minutes at OC. It is filtered and distilled in vacuo to Dry up. The residue is dissolved in 200 ecm of methanol under reflux, filtered off and concentrated to about 50 ecm, cools for an hour, sucks off, washes the precipitate with water and dries it. 4.75 g of S-chloro ^ -methoxycarbonyl-acridine are obtained in the form of a solid yellow product, slightly soluble in methanol and insoluble in water, which at 148 ° C melts.

For analysis, the product is recrystallized in methanol by heating and cooling, with the melting point remains unchanged.

Level B.

3-chloro-9-methoxycarbonyi-10-methy I-acridinium-methylsulfal

A mixture of 21 g of 3-chloro-9-methoxycarbonyl-acridine is heated and 100 ecm of methyl sulfate for 3 hours while stirring at 100 ° C. Man cools down, adds 20 ecm of toluene and then 400 ecm of ether, sucks off, washes the precipitate with ether and dries in a vacuum. 28.1 g of 3-chloro-9-methoxycarbonyl-10-methyl-acridinium-methyl sulfate are obtained, that one. as it is, used in the next stage.

The compound is in the form of a solid yellow product, is soluble in methanol, slightly löslieh in toluene and insoluble in water and ether, and melts at about 25O C ^1.

Level C

3-chloro-9-methoxycarbonyl-10-methyl-acridane

Mixing 5.3 g of 3-chloro-9-methyl-acridinium-methoxycarbonyllO methyl sulfate with 50 cc ethanol, 2.5 cc of water are added 5.3 g of potassium borohydride, while keeping the temperature at 25 ^Q C and stirred for 30 minutes. The reaction mixture is poured into water, stirred for 30 minutes and extracted with

ίο ether, washes the organic phases with water, dried over magnesium sulfate and distilled to dryness in vacuo. The residue is dissolved in 30 ecm of isopropyl ether under reflux, filtered, concentrated to 20 ecm, cooled for 30 minutes, filtered off with suction, the precipitate washed with cooled isopropyl ether and dried in vacuo. 3.18 g of 3-chloro-9-methoxycarbonyl-10-methyl-acridane are obtained, which are used as they are in the next stage.

Level D

3-chloro-9-metho ;; ycarbonyl-9 - (/> '- dimethylaminoethyl) -10-methyl-acridane (Fumarate)

10 g of 3-chloro-9-methoxycarbonyl-10-methyl-acridane are mixed with 75 ml of tetrahydrofuran and 25 ml of hexamethylphosphoric triamide, 4.6 g of potassium tert-butoxide are added at room temperature and the mixture is stirred for 30 minutes. The mixture is cooled, is 15 cc / i-Dimethylaminoäthylchlorid at a temperature below 10 ⁰ C added, bringing the reaction mixture to room temperature. The mixture is left to stand for 16 hours, water is added, the mixture is extracted with ethyl acetate, the organic phases are washed with water, dried over magnesium sulfate and distilled to dryness in vacuo.

The residue is dissolved in 25 ecm of methanol, a solution of 4 g of fumaric acid in 150 ecm of methanol is added added and the methanol is distilled off by replacing it with ethyl acetate. The ethyl acetate is concentrated to 25 ecm, seed the crystallization, cool for 30 minutes, suction off, wash the precipitate with water and dry in vacuo. 10.1 g of S-chloro-g-methoxycarbonyl ^ -i / f-dimethylaminoethyl) -IO-methyl-acridane are obtained (Fumarate that one.

4- used as it is in the next stage.

Level E.

.VChlor-9-hydroxymethyl-9 - (/ i-dirnethylarninoethyl) -10-methyl-acridane

One brings 25.7 g of S-chloro ^ -methoxycarbonyl-9 - (/ i-dimethylaminoethyl) -10-methyl-acridan (Fumarate) in suspension in 250 ecm of water, cools and adds 25 ecm of sodium hydroxide solution. One extracts with Methylene chloride, the organic phases are washed with water, dried over magnesium sulfate and distilled in a vacuum to dryness. 20 g of 3-chloro-9-methoxycarbonyl-9 - (/ f-dimethylaminoethyl) -10-methyI-acridane are obtained.

Wi One cools 200 ecm of tetrahydrofuran, gives 10 g Lithium aluminum hydride, then 20 g of 3-chloro-9-methoxycarbony! -9 - (/ i-dimethyIaminoälhyl) - 10-methylacridane, dissolved in 200 ecm tetrahydrofuran at a Temperature below +10 C. One stirs

b5 for K) minutes at 0 C and then heated for 15 minutes at reflux. It is cooled and the excess reagent is decomposed by 2 (X) ecm of tetrahydrofuran with 20% water at a temperature below

909 646/88

+ 10 ° C, filtered and distilled to dryness in vacuo. The residue is dissolved in methylene chloride, the solution is washed with water, dried over magnesium sulfate and distilled to dryness in vacuo. The residue is dissolved in 80 ecm of ethyl acetate, filtered, concentrated to 50 ecm, the crystallization is seeded, cooled for 30 minutes, filtered off with suction, the precipitate is washed with ethyl acetate, then with ether and dried in vacuo. 14.35 g of 3-chloro-9-hydroxy methyl-9 - (β- dimethy laminoethyl) -10-methyl-acridane are obtained.

For analysis, the product is recrystallized from ethyl acetate by heating and cooling.

The compound is in the form of a solid colorless product which, in ether, is soluble in methanol, insoluble and slightly soluble in water, and melts at 120 ⁰ C.

Level F

7-chloro-5-methyl-10 - (/ f-dimethylaminoethyl) -dibenzo- (b, f) -azepine

A mixture of 5 g of 3-chloro-9-hydroxymethyl is heated - 9 - (/ ί - dimethylaminoethyl) - 10 - methyl-acridane, 200 ecm of xylene and 25 g of phosphoric anhydride with stirring for 3 hours under reflux, cools down, Pour the reaction mixture onto ice, make it alkaline by adding 50 ecm of sodium hydroxide solution, and extract with it Ethyl acetate, the organic phases were washed with water, dried over magnesium sulfate and distilled in Vacuum to dryness. The residue is chromatographed on silica gel and a mixture is eluted of cyclohexane / chloroform / triethylamine (6 / 3/1). After evaporation of the solvent, 4.15 g of 7-chloro-5-methyl-10 - (/ i-dimethylaminoethyl) -dibenzo- (b, f) -azepine are obtained in the form of an amorphous product that is soluble in alcohols, chlorinated solvents, ether and benzene and insoluble in water.

Analysis door C ₁₉ H ₂₁ N ₂ Cl = 312.85:
Calculated ... N 8.95, Cl 11.33%;
found .... N 9.0, Cl 11.6%.

1. R. spectrum (chloroform):

Presence of aromatics substituted by heteroatoms and by

CH,

CH,

7-chloro-5-methyl- 10- (β -dimethylaminoethyl) -dibenzo- (b, f> azepine in 40 ecm benzene is added and the mixture is heated under reflux for 5 hours. It is cooled and the benzene solution is washed with 2N hydrochloric acid, then with Water, dried over magnesium sulfate and distilled to dryness in vacuo. 9 g of 7-chloro-5-methyl-10 - (/ iN-ethoxycarbonyl-N-methylaminoethyl) -dibenzo- (b, f) -azepine are obtained, as it is, used in the next stage.

The NMR spectrum indicates the structure indicated.

Example 6

7-chloro-5-methyl-10 - (/ i-monomethylaminoethyl) -dibenzo- (b, f) -azepine (Fumarate)

Level a

7-chloro-5-methyl-10 - (/ i-N-ethoxycarbony 1-N-methylaminoethyl) -dibenzo- (b, f) -azepine

40 ecm benzene and 8 ecm ethyl chloroformate are mixed, gives a solution of 8 g stage B

7-chloro-5-methyl-10 - (/ i-monomethylaminoethyl) -dibenzo- (b, f) -azepine (Fumarate)

10 g of 7-chloro-5-methyl-10 - (/ iN-ethoxycarbonyl - N - methylaminoethyl) - dibenzo - (b, f) - azepine are heated with a solution of 10 g of potassium hydroxide in 100 ecm of n-butanol for 20 hours Reflux. The butanol is distilled off in vacuo, the residue is taken up in ether, the ether paste is washed with water and extracted with 2N hydrochloric acid. The hydrogen chloride solutions are washed with ether, made alkaline by adding sodium hydroxide solution while stirring, and extracted with ether. The ether phases are washed with water, dried over magnesium sulfate and distilled to dryness in vacuo. 6.8 g of 7 - chloro - 5 - methyl - 10 - (β - monomethylamino-

jo ethyl) -dibenzo- (b, f) -azepine, which can be obtained by chromatography over silica gel and eluting with a mixture of chloroform / acetone / triethylamine (6/3/1) cleans.

I. R. spectrum:

Presence of NH at 3303 cm " ¹ , of aromatics at 1588 cm" ¹ and of C = C at 1563 and 1630 cm " ¹ .

4 g of 7-chloro-5-methyl-10 - (/ <- monomethylaminoethyl) -dibenzo- (b, f) -azepine are dissolved in 10 ecm of methanol, gives a solution of 1.55 g of fumaric acid in 40 ecm Add methanol, filtered, the methanol is distilled off and replaced with ethyl acetate until one is formed weak opacity. You seed the crystallization

v-, by scratching, cools for 30 minutes, sucks off, washes the precipitate with ethyl acetate with 20% methanol and dried in vacuo. 4 g of 7-chloro-5-methyl -10- (β -monomethylaminoethyl) -dibenzo- (b, f) -azepine (fumarate) are obtained.

> o For analysis, the compound is recrystallized in methanol, the melting point being unchanged remain.

The product is in the form of yellow crystals, which are soluble in methanol and ethanol, slightly soluble and which melt in water and chlorinated solvents, at 180 ⁰ C.

Analysis for C ₂₂ H _2. , O ₄ N ₂ CI = 414.89:

Calculated ... C 63.69, H 5.59, N 6.75, Cl 8.54%;
Found ... C 63.7, H 5.6, N 6.4, Cl 8.5%.

UV spectrum (ethanol):
λ max. at 214 ΐτίμ; ί = 37,000.
/ Max. At 255 -256 πΐμ; , = 32 600.
Inflection at about 326 νημ E [^, = 39.

Claims (9)

Patent claims: 1. 5-Methyl-10 - (// - alkylaminoethyl) -dibenzo- (b, f) -azepine the general formula the general formula N \ R ₂ 4 — X ' } CH ₂ CH, I J - 10 R _{1 is} an alkyl radical with 1 to 4 carbon atoms,
R _{2 is} a hydrogen or an alkyl remainder with 1 to 4 carbon atoms and X and X 'a hydrogen or chlorine atom mean, as well as the salts of these compounds with mineral acids or organic acids. 2. 5 - methyl -10 - (ß - dimethylaminoethyl) -dibenzo- (b, f) -azepine and its hydrochloride. 3. 5 - methyl -10 - (ß - monomethylaminoethyl) -dibenzo- (b, 0-azepine and its hydrochloride. 4. 2-chloro-5-methyl-10 - (/ <- dimethylamine- jo ethyl) -dibenzo- (b, f) -azepine and its fumarate. 5. 7 - Chlorine - 5 - methyl -10 - (β - dimethylaminoethyl) -dibenzo- (b, f) -azepine and its fumarate. 6. 7-chloro-5-methyl-10 - (/ y-monomethylaminoethyl) -dibenzo- (b, f) -azepine and its fumarate. 7. 8 - Chlorine - 5 - methyl -10 - (β - dimethylaminoethyl) -dibenzo- (b, f) -azepine and its fumarate. 8. Process for the preparation of the compounds according to claim 1, characterized in that one is a salt of a compound of the general formula COOaIc (H) where X and X 'have the meaning given above and "alc" means a lower alkyl radical, to a compound of the general formula (MI) 5 * 5 65 reduced, this in the presence of an alkaline agent with a 2-halo-l-dialkylaminoälhan Hai — CH, CH, N 4th \ (VI) R, where Hai represents a halogen atom, to a compound the general formula NH ₂ CH ₂ C COOaIc X '(IV) converts this compound with the aid of a hydride to a compound of the general formula NH ₂ CH ₂ C CH ₂ OH reduces this compound to a compound under the action of a dehydrating agent the general formula CH ₂ CH ₂ N (Ia) reacted and this compound, if desired, followed by the action of a dealkylating agent from an alkaline treatment, to the formation of a compound of the general formula CH ₂ CH ₂ NHR ₁ (Ib) subject and, if desired, by the action of a mineral acid or an organic Acid converts the compounds formed into their salts. 9. Pharmaceutical compositions, characterized in that they are used as the active ingredient contain at least one compound according to claim I and a pharmaceutical carrier.